ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5663A>G (p.Lys1888Arg) (rs80358791)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044713 SCV000072726 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 1888 of the BRCA2 protein (p.Lys1888Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs80358791, ExAC 0.003%). This variant has been reported in an individual affected with ovarian cancer (PMID: 18256760). ClinVar contains an entry for this variant (Variation ID: 51903). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000131719 SCV000186758 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-30 criteria provided, single submitter clinical testing The p.K1888R variant (also known as c.5663A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5663. The lysine at codon 1888 is replaced by arginine, an amino acid with highly similar properties. This variant was observed in a study of 74 Russian ovarian cancer patients (Smirnova TY et al. Bull. Exp. Biol. Med., 2007 Jul;144:83-5). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000216952 SCV000278864 uncertain significance not provided 2018-09-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5663A>G at the cDNA level, p.Lys1888Arg (K1888R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). Using alternate nomenclature, this variant would be defined as BRCA2 5891A>G. This variant was observed in an individual with ovarian cancer (Smirnova 2007). BRCA2 Lys1888Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RAD51 binding domain (Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Lys1888Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000131719 SCV000903262 likely benign Hereditary cancer-predisposing syndrome 2016-04-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779946 SCV000916891 uncertain significance not specified 2019-04-22 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5663A>G (p.Lys1888Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249646 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5663A>G has been reported in the literature in individual(s) affected with Ovarian Cancer (Smirnova_2007). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a pathogenic variant has been reported (BIC database; BRCA1 c.2934T>G, p.Tyr978Ter), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000216952 SCV001133835 uncertain significance not provided 2019-02-12 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113457 SCV000146661 uncertain significance Breast-ovarian cancer, familial 2 2002-06-20 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735571 SCV000863709 uncertain significance Breast and/or ovarian cancer 2016-05-18 no assertion criteria provided clinical testing

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